Brain clearance is reduced during sleep and anesthesia
Miao, A., Luo, T., Hsieh, B. et al. Brain clearance is reduced during sleep and anesthesia. Nat Neurosci 27, 1046–1050 (2024)
Nature Neuroscience
Published 13 May 2024
Centre Member: Prof Bill Wisden & Prof Nick Franks
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It has been suggested that the function of sleep is to actively clear metabolites and toxins from the brain. Enhanced clearance is also said to occur during anesthesia. Here, we measure clearance and movement of fluorescent molecules in the brains of male mice and show that movement is, in fact, independent of sleep and wake or anesthesia. Moreover, we show that brain clearance is markedly reduced, not increased, during sleep and anesthesia.
Characterisation of premature cell senescence in Alzheimer’s disease using single nuclear transcriptomics
Fancy, N.N., Smith, A.M., Caramello, A. et al. Characterisation of premature cell senescence in Alzheimer’s disease using single nuclear transcriptomics. Acta Neuropathol 147, 78 (2024)
Acta Neuropathologica
Published 2 May 2024
Centre Member: Prof Paul Matthews
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Cell senescence is a process during which damaged cells resist removal by normal mechanisms, lingering and potentially causing harm to neighbouring healthy cells. Ageing is the greatest single risk factor for Alzheimer’s and is associated with cell senescence. This paper reveals important new insights into the mechanisms behind senescence in Alzheimer's disease and suggests targets for future therapeutic strategies.
Bmal1 integrates circadian function and temperature sensing in the suprachiasmatic nucleus
Hoekstra, M., Ness, N., Badia-Soteras, A. et al. Bmal1 integrates circadian function and temperature sensing in the suprachiasmatic nucleus. PNAS 121, 17 (2024)
PNAS
Published 16 April 2024
Centre Member: Dr Marco Brancaccio
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Circadian core clock genes transmit 24-h rhythmic information to a plethora of clock-controlled pathways. Rhythmic expression of core clock genes is repsilient to thermal changes, a property known as temperature compensation. Here, we show that molecular pathways controlled by core clock genes are not similarly temperature compensated: Increases and decreases in temperature predictably affect their period length. Intriguingly, Bmal1, an essential core clock gene, is required to activate cold-induced transcription of the clock-controlled gene Rbm3, thus suggesting its role as an integrator between circadian function and temperature sensing. The potential rhythmic misalignment between the core clock and its target pathways, induced by temperature, may further reduce circadian proficiency in neurodegenerative diseases.
Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities
Francis, C.M., Futschik, M.E., Huang, J. et al. Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities. Nat Commun 13, 4505 (2022)
Nature Communications
Published 3 August 2022
Centre Member: Prof Paul Matthews
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People with cardiovascular disease or a higher cardiovascular disease risk also have a higher risk of dementia and Alzheimer’s disease. Brain small vessel disease, which is perhaps the most common cause of dementia and which is itself associated with Alzheimer’s, may mediate this risk. In work leading up to the current study, we performed genome-wide association studies between a range of heart muscle phenotypes and brain vascular risks, but failed to find evidence for any potential causal factors, despite heart-brain comorbidity. In this study, we perform a genetic analysis study of 32,950 participants probing the relationship between genes associated with aortic distensibility and dimensions and those for brain small vessel disease. The results we obtained suggest that altered haemodynamics and the consequent changes in cerebral blood may have direct effects on brain endothelial cells and the remodelling of small vessels.
NMDA Receptors in the Lateral Preoptic Hypothalamus Are Essential for Sustaining NREM and REM Sleep
Miracca, G,. Anuncibay-Soto, B,. et al. NMDA Receptors in the Lateral Prioptic Hypothalamus Are Essential for Sustaining NREM and REM Sleep. Journal of Neuroscience (2022)
Journal of Neuroscience
Published 1 June 2022
Centre member: Professor Bill Wisden
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Insomnia is a common affliction. Most insomniacs feel that they do not get enough sleep, but in fact, often have good amounts of sleep. Their sleep, however, is fragmented, and sufferers wake up feeling unrefreshed. It is unknown how sleep is maintained once initiated. By using knockout mouse models, we show that NMDA-type glutamate receptors in the hypothalamus are the main drivers of excitation and are required for a range of sleep properties and are, in fact, needed for both sustained NREM sleep periods, and REM sleep generation. We highlight the importance of calcium signalling via the NMDA receptors and provide a model for studying intractable insomnia.
SARS-CoV-2 is associated with changes in brain structure in UK Biobank
Douaud G, Lee S, Alfaro-Almagro F. et al. Brain imaging before and after COVID-19 in UK Biobank. Nature. (2022)
Nature
Published April 2022
Centre Member: Prof Paul Matthews
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Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology
Jiwaji, Z,. Tiware S,. et al. Reactive astroctytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology. Nature Communications. (2022)
Nature Communications
Published 10 January 2022
Centre Member: Prof Paul Matthews
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In this study we employ mouse models of ß-amyloidopathy and tauopathy to investigate the effects of these two pathologies on astrocytes and to identify the common effects, as well as any differences. We show that Aß and Tau induce overlapping astrocyte profiles associated with both deleterious (repression of bioenergetic and translation machinery) and adaptive-protective signals (induction of inflammation pathways, protein degradation and proteostasis). The potential for astrocytes, therefore, to mitigate brain dysfunction by limiting extra-neuronal Aß pathology and intra-neuronal Tau pathology point to their ability to widely influence brain health in the context of AD and offers a target for therapeutic intervention.
Circadian Clock in Brain Health and Disease
Engmann, O,. Brancaccio, M. Circadian Clock in Brain Health and Disease. Springer Cham (2021)
Springer, Cham
Published 2021
Centre Member: Dr Marco Brancaccio
Internal timekeeping mechanisms generate quasi-24-hour cyclic patterns of gene expression, physiology and behaviour adapting life on our planet to the solar cycle. While the internal machinery underpinning circadian function is ancestral and virtually present in all the realms of life, from bacteria to mammals, challenges to this adaptive system in humans are very modern: the industrial revolution has granted continuous access to (artificial) light and food, 24h flexible working patterns, and sleep restriction following societal pressure. In this book, leading experts address general principles of circadian function and the latest findings on glial timekeeping; the ways in which a modern lifestyle can impair the circadian system; the ultimate consequences of this on brain health with a broad focus on disease, including ADHD, schizophrenia, autism spectrum and mood disorders and neurodegenerative diseases. The book, edited by Marco Brancaccio, Lecturer in the Dept of Brain Sciences and Olivia Engmann, Institute of Human Genetics University Hospital Jena Friedrich Schiller University, Germany, includes chapter contributions by Imperial and UK DRI researchers, including Marc Busche (UK DRI at UCL), Bill Wisden and Nick Frank, and Marco Brancaccio (UK DRI Centre at Imperial).
Diverse human astrocyte and microglial transcriptional responses to Alzheimer’s pathology
Smith A, Davey K, et al. Diverse human astrocyte and microglial transcriptional responses to Alzheimer’s pathology. BioRxiv.
Acta Neuropathologica
Published 12 November 2021
Centre Member: Prof Paul Matthews
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Here we describe single-nuclei RNA sequencing for comprehensive characterization of transcriptomes in astrocyte and microglia nuclei isolated post mortem from neuropathologically-defined AD and control brains with a range of amyloid-beta and phospho-tau (pTau) pathology. Our analyses applied multiple strategies to elucidate the diversity of glial responses in AD.
Single nuclear transcriptional signatures of dysfunctional brain vascular homeostasis in Alzheimer’s disease
Tsartsalis S, Fancy N, Smith AM. et al. Single nuclear transcriptional signatures of dysfunctional brain vascular homeostasis in Alzheimer’s disease. BioRxiv.
BioRxiv preprint
Posted 28 October 2021
Centre Member: Prof Paul Matthews
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Vascular pathology has long been recognised as both an early and central feature of Alzheimer’s disease (AD). Here we performed single nucleus RNA sequencing of vascular cells isolated from AD and control brains enriched for nuclei from less abundant cell types including those in the vasculature. We provide a new quantitative description of the enrichment of endothelial cells (EC) for expression of genes associated with susceptibility to AD. Transcriptional signatures in AD suggest specific mechanisms for dysregulation of vascular homeostasis and angiogenesis across EC, fibroblasts and pericytes (PC). Our genomic dissection of vascular cell risk gene enrichment suggests a potentially causal role for EC in AD and defines transcriptional signatures associated with subsequent microvascular dysfunction as the disease progresses.
MungeSumstats: A Bioconductor package for the standardisation and quality control of many GWAS summary statistics
Murphy, A, Skene, N. MungeSumstats: A Bioconductor package for the standardisation and quality control of many GWAS summary statistics. BioRxiv
Bioinformatics
Published 2 October 2021
Centre Member: Dr Nathan Skene
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Genome-wide association studies (GWAS) summary statistics have democratised and accelerated genetic research. However, a lack of standardisation of the file formats used has proven problematic when running secondary analysis tools or performing meta-analysis studies. To address these issues, we have developed MungeSumstats, a Bioconductor R package for the standardisation and quality control of GWAS summary statistics. MungeSumstats can handle the most common summary statistic formats, including variant call format (VCF) producing a reformatted, standardised, tabular summary statistic file.
CHAS, a deconvolution tool, infers cell type-specific signatures in bulk brain histone acetylation studies of brain disorders
Murphy, K,. Nott, A,. Marzi, S. CHAS, a deconvolution tool, infers cell type-specific signatures in bulk brain histone acetylation studies of brain disorders. BioRxiv.
Cell type-specific Histone Acetylation Score (CHAS), a computational tool for inferring cell type-specific signatures in bulk brain H3K27ac profiles. CHAS enables deconvolution of H3K27ac in bulk brain tissue, yielding cell type-specific biological insights into brain disease-associated regulatory variation.
BioRxiv preprint
Posted 6 September 2021
Centre Member: Dr Sarah Marzi
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scFlow: A Scalable and Reproducible Analysis Pipeline for Single-Cell RNA Sequencing Data
Khozoie C, Fancy Nuran,. et al. scFlow: A Scalable and Reproducible Analysis Pipeline for Single-Cell RNA Sequencing Data. BioRxiv.
BioRxiv preprint
Posted 19 August 2021
Centre Member: Dr Nathan Skene & Prof Paul Matthews
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Here we present the scFlow toolkit, which provides a higher level of abstraction on top of popular single-cell packages within an R ecosystem and an nf-core/scflow Nextflow pipeline to enable compute infrastructure-independent deployment of tools flexibly across platforms. The pipeline leverages the advantages of containerization and the potential of Cloud computing for easy orchestration and scaling of the analysis of large case/control datasets by even non-expert users. It provides a transparent approach to complex scRNASeq analyses to contribute to reproducible science in the area.
Widespread cell stress and mitochondrial dysfunction in early Alzheimer’s Disease
Venkataraman, A,. Mansur, A,. Rizzo, G. et al. Widespread cell stress and mitochondrial dysfunction in early Alzheimer’s Disease. MedRxiv.
MedRxiv preprint
Posted 13 August 2021
Centre Member: Prof Paul Matthews
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To understand the relationships between cell stress and biochemical pathology of AD, we quantified the in vivo density of the endoplasmic reticulum stress marker, the sigma 1 receptor (S1R) using [11C]SA4503 PET, as well as that of mitochondrial complex I (MC1) with [18F]BCPP-EF and the pre-synaptic vesicular protein SV2A with [11C]UCB-J in patients with early AD and in cognitively normal controls. The study provides novel in vivo evidence for widespread cellular stress and bioenergetic abnormalities in early AD and how they may be clinically meaningful.
Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases
Feleke, R., Reynolds, R.H., Smith, A.M. et al. Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases. Acta Neuropathol (2021)
Acta Neuropathalogica
Published 26 July 2021
Centre Member: Prof Paul Matthews & Prof John Hardy
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This important work provides new insight into the cellular pathology of Parkinson’s dementia.
Astrocyte reactivity with late-onset cognitive impairment assessed in vivo using 11C-BU99008 PET and its relationship with amyloid load
Calsolaro, V., Matthews, P.M., Donat, C.K. et al. Astrocyte reactivity with late-onset cognitive impairment assessed in vivo using 11C-BU99008 PET and its relationship with amyloid load. Mol Psychiatry (2021)
Molecular Psychiatry
Published 15 July 2021
Centre Member: Prof Paul Matthews
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11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer's disease, we studied cognitively impaired (CI) subjects andage-matched healthy controls (HC) with 3T magnetic resonance imaging (MRI), 18F-florbetaben and 11C-BU99008 PET. Our proof-of-concept study provides direct evidence that 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer's disease and confirms that increased astrocyte reactivity is found particularly in cortical regions with high Aβ load.
Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging
McCartney DL, Min JL, et al. Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging. Genome Biol. 22,1 (2021)
Genome Biology
Published 29 June 2021
Centre Member: Prof Paul Elliott
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Aging is the single largest risk factor for Alzheimer’s and other late life neurodegenerative diseases. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. The international collaborative group leveraged DNA methylation and SNP data from more than 40,000 Individuals for evidence of shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function.
Activated microglia do not increase 18 kDa translocator protein (TSPO) expression in the multiple sclerosis brain
Nutma E, Gebro E, et al. Activated microglia do not increase 18 kDa translocator protein (TSPO) expression in the multiple sclerosis brain. Glia. 69,10 (2021)
Glia
Published 19 June 2021
Centre Member: Prof Paul Matthews
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MS is a chronic inflammatory neurodegenerative disease prominently involving microglial activation in the pathology. Rhe 18 kDa Translocator protein (TSPO) is a frequently used target for monitoring innate immune responses with PET imaging. The frequent assumption that increased TSPO expression in the human CNS reflects pro-inflammatory activation of microglia has been extrapolated from rodent studies. However, TSPO expression does not increase in activated human microglia in vitro. Here we describe a comprehensive investigation in the brain in multiple sclerosis (MS) lesions which reveals that TSPO is not restricted to pro-inflammatory microglia/macrophages, but also present in homeostatic or reparative microglia.
A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation
Yao, Z., van Velthoven, C., Nguyen, T. et al. A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation. Cell. 184,12 (2021)
Cell
Published 10 June 2021
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We found that cell types are organized in a hierarchical manner and exhibit varying degrees of discrete or continuous relatedness with each other. Such molecular relationships correlate strongly with the spatial distribution patterns of the cell types, which can be region-specific, or shared across multiple regions, or part of one or more gradients along with other cell types.
Brain imaging before and after COVID-19 in UK Biobank
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This report involving the UK DRI Centre Director in his role for UK Biobank provides the first well-controlled data testing for effects of SARS-CoV-2 infection on brain structure. Uniquely amongst studies to date, the UK Biobank embedded design allow direct comparison of pre- and post- exposure brain scans quantitatively. Although the data still are preliminary for the continuing study, different contrasts converge to provide evidence for brain volume loss with exposure. Changes of this type could explain effects of COVID on cognitive performance, even as the acute disease resolves.
Alcohol consumption in the general population is associated with structural changes in multiple organ systems
Evangelos Evangelou, Hideaki Suzuki, Wenjia Bai, Raha Pazoki, He Gao, Paul M Matthews MD, PhD, Paul Elliott
Study lead, Professor Paul Elliot, Group Leader from UK Dementia Research Institute at Imperial, Chair in Epidemiology and Public Health Medicine at Imperial, said:
“In the UK and many places worldwide, it is recommended that men and women avoid more than one or two alcoholic drinks a day. Our results suggest that intake below these levels could still lead to pathological structural and functional changes across multiple organs. Therefore, we recommend that current public health guidelines around alcohol consumption are reconsidered.”
Study co-author Professor Paul Matthews, Centre Director at UK Dementia Research Institute at Imperial College London, Edmond and Lily Safra Chair, NIHR Senior Investigator, and Head of the Department of Brain Sciences, said:
“We now are at a point where we can begin to define environmental and lifestyle factors contributing to dementia in precise ways that can help people take positive steps to reduce their risk. This study is not about something that is abstract - it graphically highlights harmful effects of alcohol for health of the brain and body even when it is consumed in moderation, a message that should resonate most of us.”
UK DRI Centre at Imperial Student Review
Neurological consequences of COVID-19 infection
Jiabin Tang, Shivani Patel, Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK, UK Dementia Research Institute, Imperial College London, London, UK
This well-researched paper reviews the biology of SARS-CoV-2, highlighting the additional risks the pandemic has posed for people with dementia and exploring provocative data suggesting that infections could contribute to triggering or accelerating neurodegenerative pathology. This is the first in a series of student-initiated reviews of topical areas in the science of dementia.
Altered perivascular fibroblast activity precedes ALS disease onset
Månberg, A., Skene, N., Sanders, F. et al. Altered perivascular fibroblast activity precedes ALS disease onset. Nat Med 27, 640–646 (2021)
Nature Medicine
Published 15 April 2021
Centre Member: Dr Nathan Skene
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This report describes the involvement of perivascular fibroblasts (PVF), a recently recognised population of blood vessel associated cells encoding main components of the extracellular matrix, in the earliest stages of ALS. We applied the EWCE method (which I had previously developed) to transcriptomic data and discovered that PVFs are affected in both humans with ALS and multiple mouse models of the disease. We demonstrated that the PVF marker proteins SPP1 accumulates in enlarged perivascular spaces with ALS and that plasma SPP1 concentrations predicted disease course in four independent cohorts. This innovative work focuses attention on the pathological importance of a newly recognised cell population and provides evidence for a plasma biomarker that could be used with their therapeutic modulation.
Metabolome-wide association study on ABCA7 demonstrates a role for ceramide metabolism in impaired cognitive performance and Alzheimer's disease
Dehghan, A,. Pinto, R,. Karaman, I. et al. Metabolome-wide association study on ABCA7 demonstrates a role for ceramide metabolism in impaired cognitive performance and Alzheimer's disease. MedRxiv. (2021)
MedRxiv preprint
Posted 9 April 2021
Centre Members: Prof Paul Elliott, Prof Paul Matthews, Prof Julian Griffin
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In this study, we apply large scale metabolome-wide association analysis to genetic variants identified for Alzheimer’s disease. We report a set of small molecules including lactosylceramides to associate with genetic variants at ABCA7 both in humans and mouse model, We show that lactosylceramides are associated with cognitive decline in humans and provide evidence for their causal role in Alzheimer’s disease using Mendelian randomisation. Overall, the paper introduces ceramide metabolism as a pathway that contributes to cognitive performance and risk of Alzheimer’s disease.
Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer’s disease.
Davis, N., Mota, B.C., Stead, L. et al. Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer’s disease. J Neuroinflammation 18, 73 (2021)
Journal of Neuroinflammation
Published 17 March 2021
Centre Member: Dr Samuel Barnes
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Recent collaborative project probing the role of astrocytes in Aβ pathology and dendritic spine density. This project sets the foundation for ongoing collaborative work, probing the role of astrocytes in destabilized neuronal activity in vivo in preclinical rodent models of amyloidosis.
The aging mouse brain: cognition, connectivity and calcium
Radulescu CI, Cerar V, Haslehurst P, et al. The aging mouse brain: cognition, connectivity and calcium. Cell Calcium. 94 (2021)
Cell Calcium
Published March 2021
Centre Member: Dr Samuel Barnes
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Recent paper highlighting an important knowledge gap in our understanding of age-related changes in homeostatic control of neuronal firing-rate.
Multi-scale network imaging in a mouse model of amyloidosis
Doostdar N, Airey J, Radulescu CI, et al. Multi-scale network imaging in a mouse model of amyloidosis. Cell Calcium. 95 (2021)
Cell Calcium
Published 11 Feb 2021
Centre Member: Dr Samuel Barnes
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Recent paper showing the multi-scale imaging approaches and their interface with in vivo measures of amyloid pathology and cognitive testing are established. This project sets the foundation for ongoing collaborative work testing the potential of targeted TI stimulation to modulate amyloid-related neuronal hyperactivity.
Nuclei isolation of multiple brain cell types for omics interrogation
Nott, A., Schlachetzki, J.C.M., Fixsen, B.R. et al. Nuclei isolation of multiple brain cell types for omics interrogation. Nat Protoc 16, 1629–1646 (2021)
Nature Protocols
Published 25 January 2021
Centre Member: Dr Alexi Nott
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There has been intense interest in elucidating mechanisms that link human non-coding genetic variation to the risk of neurodegenerative and psychiatric diseases. Towards this effort, we establish a protocol for isolating nuclei of specific cell types from frozen human brain tissue. The nuclei isolation protocol allows cell type-specific profiling of neurons, microglia, oligodendrocytes and astrocytes, which is compatible with fresh and frozen samples obtained from either resected or postmortem brain tissue. We previously used this approach to show that genetic variants associated with an increased risk of AD were largely confined to microglia enhancers, whereas genetic risk variants for psychiatric disorders were enriched in neuronal enhancers.
Alcohol consumption is associated with structural changes in various organ systems: A population-based study in UK Biobank
Evangelou, E,. Suzuki, H,. Bai, W. et al. Alcohol consumption is associated with structural changes in various organ systems: A population-based study in UK Biobank. MedRxiv. (2021)
MedRxiv preprint
Posted 20 January 2021
Centre Member: Prof Paul Matthews & Prof Paul Elliott
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In this study of brain and other imaging in relation to alcohol intake in a large general population study (UK Biobank), we found that increasing alcohol intake was associated with lower normalised brain volume across the range of population alcohol intakes, even within “safe drinking” limits, with no apparent threshold.
Non-invasive suppression of essential tremor via phase-locked disruption of its temporal coherence
Schreglmann, S.R., Wang, D., Peach, R.L. et al. Non-invasive suppression of essential tremor via phase-locked disruption of its temporal coherence. Nat Commun 12, 363 (2021)
Nature Communications
Published 13 January 2021
Centre Member: Dr Nir Grossman
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Here, we first report a method to track the phase of neural oscillations in real-time, then show that the aberrant neural oscillation that hallmarks essential tremor (ET) syndrome can be transiently suppressed via transcranial electrical stimulation of the cerebellum phase-locked to the tremor. We then show that the suppression of ET is mechanistically attributed to a disruption of the temporal coherence of the aberrant oscillations in the olivocerebellar loop. The phase-locked driven disruption of temporal coherence provides a powerful neuromodulatory strategy to mitigate aberrant neural oscillations underpinning the pathology and symptoms in AD and PD.
Molecular characterization of selectively vulnerable neurons in Alzheimer’s Disease
Leng, K., Li, E., Eser, R. et al. Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease. Nat Neurosci 24, 276–287 (2021)
Nature Neuroscience
Published 11 January 2021
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Alzheimer’s disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus – brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively – from individuals spanning the neuropathological progression of AD.
Cerebral small vessel disease genomics and its implications across the lifespan
Sargurupremraj, M., Suzuki, H., Jian, X. et al. Cerebral small vessel disease genomics and its implications across the lifespan. Nat Commun 11, 6285 (2020).
Nature Communications
Published 8 December 2020
Centre Member: Prof Paul Matthews
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This study describes new genetic risk loci for cerebral small vessel disease using MRI white matter hyperintensities as an intermediate or surrogate phenotype. A Mendelian Randomisation analysis provides the first direct evidence that the pathology underlying these white matter hyperintensities is potentially causal for Alzheimer’s disease.
Unbalanced SSFP for super‐resolution in MRI
Lally, PJ, Matthews, PM, Bangerter, NK. Unbalanced SSFP for super‐resolution in MRI. Magn Reson Med. 85, 2477– 2489 (2021)
Magnetic Resonance in Medicine
Published 20 November 2020
Centre Member: Prof Paul Matthews
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Early detection and in vivo characterisation of neurodegenerative pathology in smaller regions of the brain (e.g., entorhinal cortex, substantia nigra) has been limited by clinical MRI resolution. This paper describes a potentially transformative method for combining paired SSFP scans to achieve large gains in spatial resolution in clinically practical times, promising to make quantitative studies of structures in these regions possible.
Accelerated MRI-predicted brain ageing and its associations with cardiometabolic and brain disorders
Kolbeinsson, A., Filippi, S., Panagakis, Y. et al. Accelerated MRI-predicted brain ageing and its associations with cardiometabolic and brain disorders. Sci Rep 10, 19940 (2020)
Scientific Reports
Published 17 November 2020
Centre Member: Prof Paul Matthews & Prof Paul Elliott
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In this paper, we developed a deep neural network model trained on brain MRI scans of healthy people to predict “healthy” brain age. The cerebellum, hippocampus, amygdala and insular cortex showed the largest contribution to brain aging. Moreover, we showed that diastolic blood pressure accelerates brain aging. The findings could help to better define risk factors for late life brain aging diseases. Moreover, this information (brain age) could be used to stratify people who could potentially benefit from timely interventions to prevent diseases that are due to the aging brain, including dementia.
Hypothalamic NMDA receptors stabilize NREM sleep and are essential for REM sleep
Miracca, G,. Anuncibay Soto, B,. Tossell, K. et al. Hypothalamic NMDA receptors stabilize NREM sleep and are essential for REM sleep. BioRxiv.
BioRxiv preprint
Posted 20 October 2020
Centre Member: Prof Bill Wisden
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In this paper, we describe the generation of mice with permanently high sleep-wake fragmentation (insomnia) but overall normal amounts of sleep.
Sleep, major depressive disorder and Alzheimer’s disease: a Mendelian randomisation study
Huang, Jian,. Zuber V., Matthews PM. et al. “Sleep, major depressive disorder, and Alzheimer disease: A Mendelian randomization study.” Neurology. 95,14 (2020)
Neurology
Published 6 October 2020
Centre Member: Prof Paul Matthews & Prof Paul Elliott
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This provocative study challenges popular interpretations of associations between disturbed sleep and dementia by showing, through Mendelian randomisation, that these must arise incidently through common relationships with other factors. No evidence for causal links between altered sleep patterns and Alzheimer’s disease was found.
Single-nucleus RNA-seq is not suitable for detection of microglial activation genes in humans
Thrupp, N,. Sala Frigerio, C,. Wolfs, L. et al. Single-nucleus RNA-seq is not suitable for detection of microglial activation genes in human. 32, 13 (2020)
Cell Reports
Published 29 September 2020
Centre Member: Prof Paul Matthews & Dr Nathan Skene
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This already influential report contrasts transcripts obtained from scRNA and snRNA sequencing of microglia to show that the latter not only are sparse, but also are biased to low enrichment in transcripts related to immune activation. These results thus highlight the need for larger numbers of samples with snRNASeq, as well as re-emphasising the need for care in interpreting the transcriptional data.
An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer's disease
Nativio, R., Lan, Y., Donahue, G. et al. An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease. Nat Genet 52, 1024–1035 (2020).
Nature Genetics
Published 28 September 2020
Centre Member: Dr Raffaella Nativio
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This paper show that different histone modifications are differently associated with healthy ageing and Alzheimer’s disease. Specifically, H3K27ac and H3K9ac promote disease pathways through dysregulation of transcription and chromatin-gene feedback loops.
A population-based phenome-wide association study of cardiac and aortic structure and function
Bai, W., Suzuki, H., Huang, J. et al. A population-based phenome-wide association study of cardiac and aortic structure and function. Nat Med 26, 1654–1662 (2020).
Nature Medicine
Published 24 August 2020
Centre Member: Prof Paul Matthews
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Chronic brain hypoperfusion and consequent hypoxia/ischemia could increase the risk of dementia. Here we analysed cardiovascular magnetic resonance images from UK Biobank, using an automated machine-learning-based analysis pipeline. The findings address heart–brain health interactions and indicated that cardiovascular function is related to cognitive function.
The VIP-VPAC2 neuropeptidergic axis defines and generates emergent circadian network properties of the mammalian suprachiasmatic nucleus
Patton, A.P., Edwards, M.D., Smyllie, N.J. et al. The VIP-VPAC2 neuropeptidergic axis is a cellular pacemaking hub of the suprachiasmatic nucleus circadian circuit. Nat Commun 11, 3394 (2020)
Nature Communications
Published 7 July 2020
Centre Member: Dr Marco Brancaccio
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In this paper we showed by genetic manipulations in vivo and ex vivo that astrocytes are bona fide pacemakers, capable of restoring circadian function in neurons and drive mammalian behaviour to their intrinsic tempo. Methods used in this paper will be used across all the objectives.
Genetically determined blood pressure, antihypertensive drug classes and risk of stroke subtypes
Marios K. Georgakis, Dipender Gill, Alastair J.S. Webb, Evangelos Evangelou, Paul Elliott, Cathie L.M. Sudlow, Abbas Dehghan, Rainer Malik, Ioanna Tzoulaki, Martin Dichgans. Neurology 95,4 (2020)
Neurology
Published 1 July 2020
Centre Member: Prof Paul Elliott
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Stroke is a risk factor for vascular dementia and Alzheimer’s disease. In this study, we investigated whether BP-lowering through different antihypertensive drug classes on stroke risk varies by stroke aetiology and found that calcium channel blockers are associated with lower risk of stroke, a finding that has implications for dementia prevention.
Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior
Yu, X., Ba, W., Zhao, G. et al. Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior. Mol Psychiatry (2020).
Molecular Psychiatry
Published 17 June 2020
Centre Member: Prof Bill Wisden
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Delirium, which shares some features with mania, is associated with neurodegenerative diseases. This report explores the mechanistic role for the ventral tegmental area (VTA), an important source of dopamine which regulates goal- and reward-directed and social behaviors, wakefulness, and sleep in the latter. It also introduces a novel mouse model of insomnia of use for AD studies.
Sleep and thermoregulation
Harding EC, Franks NP, Wisden W. Sleep and thermoregulation. Curr Opin Physiol. 15,7-13. (2020)
Current Opinion in Physiology
Published 15 June 2020
Centre Member: Prof Bill Wisden
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Sleep disruption is a central and potentially contributory factor to neurodegenerative diseases. An aspect too little explored to date has been how consequences for thermoregulation may influence pathology. The fundamental basis for this is outlined here.
Genetic identification of cell types underlying brain complex traits yields insights into the etiology of parkinson’s disease
Bryois, J., Skene, N.G., Hansen, T.F. et al. Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease. Nat Genet 52, 482–493 (2020)
Nature Genetics
Published 27 April 2020
Centre Member: Dr Nathan Skene
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This paper showed for the first time (1) that monoaminergic neurons are genetically implicated in sporadic Parkinson’s disease, (2) that rare variants associated with Parkinsonism also associate with monoaminergic neurons, (3) that oligodendrocytes and enteric neurons are also implicated in sporadic Parkinson’s disease, (4) that oligodendrocyte associated transcripts are upregulated prior to degeneration of dopaminergic neurons at braak stage 1 in the substantia nigra.
Associations of Regional Brain Structural Differences With Aging, Modifiable Risk Factors for Dementia, and Cognitive Performance
Suzuki H, Venkataraman AV, Bai W, et al. Associations of Regional Brain Structural Differences With Aging, Modifiable Risk Factors for Dementia, and Cognitive Performance. JAMA Netw Open. (2019)
JAMA Network Open
Published 11 December 2019
Centre Member: Prof Paul Matthews
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The question of whether specific regions of brains are more vulnerable to exposures to modifiable risks factors associated with dementia was addressed with a study of over 8000 people. We demonstrated that clinical history hypertension, diabetes, obesity and alcohol all associated with focal, regional atrophic changes within areas known also to be vulnerable to Alzheimer’s pathology.
Associations of regional brain structural differences with aging, modifiable risk factors for dementia, and cognitive performance
Suzuki, H,. Venkataraman, AV,. Bai, W. et al. Associations of regional brain structural differences with aging, modifiable risk factors for dementia, and cognitive performance. JAMA Network. (2019)
JAMA Network
Published 2 December 2019
Centre Member: Dr Ashwin Venkataraman
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The neuropathology of Alzheimer's disease has a characteristic pattern of development in the brain. We hypothesised that this may in part reflect a differential association (and, by implication) susceptibility to influences of environmental or lifestyle risk factors. As a first test of this hypothesis, we mapped the relationships between risk factors for AD and regional brain structural changes in a large UK population. The results support a concept of environment and lifestyle influences on the differentially expressed pathology of the disease.
Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration
Noordam R, Evangelou E, Elliott P, Redline Set al., Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration, Nature Genetics, Vol: 10, ISSN: 1061-4036 (2019)
Nature Communications
Published 12 November 2019
Centre Member: Prof Paul Elliott
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Sleep disorders are more prevalent in those ageing with chronic diseases, including both cardiovascular disease and Alzheimer's disease. To test for potential causal relationships between genetic susceptibility factors, this first exploration of lipid profiles associated with sleep pathology demonstrated an interaction between genes associated with short sleep and triglycerides.
Probabilistic cell typing enables fine mapping of closely related cell types in situ
Qian X, Harris KD, Hauling T, et al. Probabilistic cell typing enables fine mapping of closely related cell types in situ, Nature Methods, 17, 101-106 (2020)
Nature Methods
Published November 2019
Centre Member: Dr Nathan Skene
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This important paper outlines a generalisable strategy for in situ sequencing of the transcriptome and demonstrates its application for decoding of the spatial organisation of closely related cortical neutrons in the rodent. What will be important in future work is to understand whether this can be extended to map differences in neuronal or glial state with disease.
Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice
Kundu, P,. Ung Lee, H,. Garcia-Perez, I. et al. Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice. Science Translational Medicine. 11, 518 (2019)
Science Translational Medicine
Published November 2019
Centre Member: Prof Elaine Holmes
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This important paper defines FGF21 as a key hormone mediating responses to short chain fatty acids (SCFA) for signalling to promote neurogenesis. It demonstrates a novel link between the gut microbiome and brain health and suggests the potential for using SCFA or similar molecules to promote functional gains in hippocampal dependent functions.
Alcohol metabolism contributes to brain histone acetylation
Mews P, Egervari G, Nativio R..et al. Alcohol metabolism contributes to brain histone acetylation. Nature.574(7780):717-721 (2019)
Nature
Published October 2019
Centre Members: Prof Paul Matthews & Dr Raffaella Nativio
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Alcohol is the most widely used drug and the most common drug of abuse. Alcohol also has pervasive effects on the brain and excessive use is associated with Alzheimer's disease and other dementias. This fundamentally important report links alcohol consumption directly with epigenetic modifications of neutrons with functional changes related to cognition. In doing so, it offers a clear illustration between an environmental factor and molecular mechanisms of cognitive impairment.
N-Terminal Ubiquitination of Amyloidogenic Proteins Triggers Removal of their Oligomers by the Proteasome Holoenzyme
Ye Y, Klenerman D, Finley D, N-Terminal Ubiquitination of Amyloidogenic Proteins Triggers Removal of Their Oligomers by the Proteasome Holoenzyme, Journal of Molecular Biology, 432, 585-596 (2020)
Journal of Molecular Biology
Published 10 September 2019
Centre Member: Dr Yu Ye
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In vivo detection of cerebral tau pathology in long-term survivors of traumatic brain injury
Gorgoraptis N, Li LM, Whittington A, et al., In vivo detection of cerebral tau pathology in long-term survivors of traumatic brain injury, Science Translational Medicine, 11, 1-14 (2019)
Science Translational Medicine
Published 4 September 2019
Centre Member: Prof Paul Matthews
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Chronic inflammation in multiple sclerosis - seeing what was always there
Matthews P, Chronic inflammation in multiple sclerosis — seeing what was always there, Nature Reviews Neurology, 15, 582-593 (2019)
Nature Reviews Neurology
Published 16 August 2019
Centre Member: Prof Paul Matthews
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While this review addresses the challenge of monitoring chronic inflammation in multiple sclerosis specifically, the approaches covered are relevant to the full range of neurodegenerative diseases associated with neurodegeneration. Written for a medical research audience, it assumes little background in imaging but is heavily referenced for follow up. The explicit integration of neuropathology and clinical imaging is intended to enhance the meaningfulness of the latter.
Modulation without surgical intervention
Grossman N, Modulation without surgical intervention Noninvasive deep brain stimulation can be achieved via temporally interfering electric fields, SCIENCE, Vol: 361, Pages: 461-462, (2019)
Science
Published 3 August 2019
Centre Member: Dr Nir Grossman
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This personal review provides a short, approachable introduction to UK DRI Fellow Grossman's novel interference transcranial alternating current stimulation method for steerable, targeted deep brain modulation. Current work now is exploring ways in which this and related methods could be used as safe, low cost interventions to reduce symptoms or therapeutically modify the progression of Alzheimer's and Parkinson's diseases.
New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders
Evangelou E, Gao H, Blakeley P, et al., New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders, Nature Human Behaviour. 3, 950-961 (2019)
Nature Human Behaviour
Published 29 July 2019
Centre Members: Prof Paul Matthews & Prof Paul Elliott
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This novel study integrates data from a wide range of population-based resources to discover genes associated with alcohol consumption. Striking overlap with genes associated with dementias (MAPT), schizophrenia (SLC39, DRD2) and brain development (BDNF) were found. Exploration of the independent associations of SNPs related to alcohol consumption and variation in brain structure, particularly for the basal ganglia, were found. These suggest common mechanistic factors may underly the epidemiologically observed association of Alzheimer's disease with heavy alcohol consumption.
Serum metabolic signatures of coronary and carotid atherosclerosis and subsequent cardiovascular disease
Tzoulaki, I., Castagné, R., Boulangé, C. et al. Serum metabolic signatures of coronary and carotid atherosclerosis and subsequent cardiovascular disease. European heart journal, 40,34: 2883–2896 (2019)
European Heart Journal
Published 18 May 2019
Centre Member: Prof Paul Elliott
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Atherosclerosis is significantly associated with Alzheimer’s disease and dementia. Here, we conducted an MWAS on carotid IMT. a measure of atherosclerosis. Highlighted metabolites were in lipid and carbohydrate metabolism, branched chain, and aromatic amino acid metabolism, as well as oxidative stress and inflammatory pathways. These findings might point to shared pathways for CVD and dementia
Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models
Hutson, TH,. Kathe, C,. Palmisano, I,. et al. Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models. Science Translational Medicine. 11, 487 (2019)
Science Translational Medicine
Published March 2019
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This is one in a series of exciting reports overturning decades of dogma suggesting the environment of the CNS is the major factor limiting neuronal regeneration. Findings in this study demonstrate the regenerative capacity of the rodent spinal cord can be enhanced by epigenetic reprogramming of the neurons.
Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways
Jansen PR, Watanabe K, Stringer S, et al., Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways, Nature Genetics. 51, 394 (2019)
Nature Genetics
Published March 2019
Centre Member: Dr Nathan Skene
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Edmond and Lily Safra Research Fellow Nathan Skene was part of an international team that has increased characterisation of the SNPs associated with insomnia substantially, the second most prevalent mental disorder, in a population of unprecedented size. Using the increased understanding of the genetic architecture of insomnia, causal effects of insomnia on a range of clinical associated disorders, such as depression, diabetes and cardiovascular disease, were able to be tested using Mendelian Randomisation.
Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk
Jansen IE, Savage JE, Watanabe K, et al., Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk, Nature Genetics, 51, 404-413, (2019)
Nature Genetics
Published March 2019
Centre Member: Dr Nathan Skene
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This report describes a further advance in the understanding of the genetic architecture of Alzheimer's disease with identification of 29 risk loci, implicating over 200 potential causal genes. These reinforce the importance of lipid-related processes and those for degradation of amyloid protein. Overall, Mendelian randomisation suggests a potential protective effect on cognition in AD for these genes.
The Mammalian Circadian Timing System and the Suprachiasmatic Nucleus as Its Pacemaker
Hastings MH, Maywood ES, Brancaccio M, The mammalian circadian timing system and the suprachiasmatic nucleus as its pacemaker, Biology, Vol: 8 (2019)
Biology (Basel)
Published 11 March 2019
Centre Member: Dr Marco Brancaccio
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This is a landmark paper that provides compelling evidence that astrocytes are integral components of the "master" circadian clock of the suprachiasmatic nucleus. The experiments further demonstrate how multi-cellular circuits in the SCN work together to generate a consensus pacemaker.
Ultrasonic sculpting of virtual optical waveguides in tissue
Chamanzar, M., Scopelliti, M., Bloch, J. et al. Ultrasonic sculpting of virtual optical waveguides in tissue. Nat Commun. 10, 92 (2019)
Nature Communications
Published 9 January 2019
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An innovative acousto-optical study published in Nature Communications shows how ultrasound can be used as a virtual wave guide for light signals in biological tissues. Creating ultrasonic standing waves focused the light stimulus and decreased its scattering in deeper tissue layers. Moreover, synchronising laser pulses with the ultrasonic transducer at different phases enabled generation of complex light trajectories. These features may be extremely useful for developing novel methods of brain stimulation/imaging in deep brain structures that would not require invasive manipulations.
Filamentous Aggregates Are Fragmented by the Proteasome Holoenzyme
Cliffe R, Sang JC, Kundel F, et al. Filamentous Aggregates Are Fragmented by the Proteasome Holoenzyme. Cell Rep. 26(8):2140-2149 (2019)
Cell Reports
Published 19 February 2019
Centre Member: Dr Yu Ye
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This important report from new UK DRI at Imperial Fellow, Ye Yu, provides evidence for a novel ATP-dependent proteasomal fragmentation function able to disassemble fibrillar structures including those of tau and alpha-synuclein, into smaller species. These smaller species also were found to be more cytotoxic, suggesting that inhibiting this function of proteosomes could be therapeutic.
Genetic risk variants for brain disorders are enriched in cortical H3K27ac domains
Hannon, E., Marzi, S.J., Schalkwyk, L.S. et al. Genetic risk variants for brain disorders are enriched in cortical H3K27ac domains. Mol Brain 12, 7 (2019).
Molecular Brain
Published 28 January 2019
Centre Member: Dr Sarah Marzi
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This report from soon-to-be-appointed Safra-UK DRI Fellow Sarah Marzi addresses the roles of genetic variants in non-coding regions in influencing susceptibility for brain disorders. By mapping lysine H3K27 acetylation (H3K27ac), a robust marker for active enhancers and promoters, in the human entorhinal cortex, the investigators discovered that risk alleles for brain disorders were preferentially located in regions of regulatory/enhancer function, further supporting the hypothesis that genetic variants for these phenotypes influence gene regulation in the brain.
Cell-autonomous clock of astrocytes drives circadian behavior in mammals
Brancaccio, M,. Edwards, M,. Patton, A. et al. Cell autonomous clock of astrocytes drives circadian behaviour in mammals. Science. 363, 6423: 187-192 (2019)
Science
Published 11 January 2019
Centre Member: Dr Samuel Barnes
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In this paper we showed by genetic manipulations in vivo and ex vivo that astrocytes are bona fide pacemakers, capable of restoring circadian function in neurons and drive mammalian behaviour to their intrinsic tempo. Methods used in this paper will be used across all the objectives
GABA and glutamate neurons in the VTA regulate sleep and wakefulness
Yu X, Li W, Ma Y, et al. GABA and glutamate neurons in the VTA regulate sleep and wakefulness. Nature Neuroscience, 22, 106-119, (2019)
Nature Neuroscience
Published January 2019
Centre Members: Prof William Wisden & Prof Nicholas Franks
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This compelling study characterises brain circuits responsible for wakefulness in the most, suggesting that GABAergic neutrons in the ventral tegmental area (VTA) both directly inhibit glutamatergic or dopaminergic neutrons in the VTA and project further into the lateral hypothalamus. The novel results show clearly that the VTA is responsible both for sleep and wakefulness.
A histone acetylome-wide association study of Alzheimer's disease identifies disease-associated H3K27ac differences in the entorhinal cortex
Marzi, S.J., Leung, S.K., Ribarska, T. et al. A histone acetylome-wide association study of Alzheimer’s disease identifies disease-associated H3K27ac differences in the entorhinal cortex. Nat Neurosci. 21, 1618–1627 (2018)
Nature Neuroscience
Published November 2018
Centre Member: Dr Sarah Marzi
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Here Marzi and her colleagues quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) in entorhinal cortex samples from Alzheimer's disease (AD) cases and matched control. Their analysis highlighted a highly significant enrichment of AD risk variants in entorhinal cortex H3K27ac peak regions. With this background, the authors present a framework for genome-wide studies of histone modifications in complex disease.
Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease
Kivipelto M, Mangialasche F, Ngandu T. Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease. Nat Rev Neurol. 14(11):653-666. (2018)
Nature Reviews Neurology
Published November 2018
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Environmental and lifestyle factors may make up to a 30% contribution to the overall risk of Alzheimer’s disease. Whenever I explain this, people inevitably ask, “What can I do to lower my own risk? Is there evidence that anything works?”. This readable review led by Mia Kivipelto (Imperial College and Karolinska Institute) sets out the current state of knowledge, including the encouraging results from the Finnish FINGER study that suggest the lifestyle changes even in middle age can have an effect.
In vivo modeling of human neuron dynamics and Down syndrome
Real R, Peter M, et al., In vivo modeling of human neuron dynamics and Down syndrome, Science, 362 (2018)
Science
Published 16 November 2018
Centre Member: Dr Samuel Barnes
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"Humanising" mice to create disease models more predictive of human neuropathology has long been a goal. This report demonstrates that human iPSC-derived cortical neutrons can be integrated into the growing rodent brain and establish functional synaptic networks in a recapitulation of developmental programmes. Moreover, it illustrates how abnormalities in this behaviour can be used to characterise disease (Down's syndrome).
Stimulation to Treat Neurological and Psychiatric Conditions
Grossman N, Okun MS, Boyden ES, Translating Temporal Interference Brain Stimulation to Treat Neurological and Psychiatric Conditions, JAMA Neurology, 75, 1307-1308, (2018)
JAMA Neurology
Published 1 November 2018
Centre Member: Dr Nir Grossman
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This authoritative review by leaders in the field highlights recent advances in one of the most promising areas of non-invasive human brain stimulation with a specific focus on the method of temporal interference stimulation proposed by the author.
Epigenetic Regulation in Neurodegenerative Diseases
Berson A, Nativio R, Berger SL, Bonini NM. Epigenetic Regulation in Neurodegenerative Diseases. Trends Neurosci. 41(9):587-598. (2018)
Trends in Neurosciences
Published September 2018
Centre Member: Dr Raffaella Nativio
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This highly readable review outlines the growing understanding of how epigenetic factors influence brain function and disease.
Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits
Evangelou E, Warren HR, Mosen-Ansorena D, et al. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nature Genetics. vol 50, pg 1412 (2018)
Nature Genetics
Published 17 September 2018
Centre Member: Prof Paul Matthews
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Elevated blood pressure is a major risk factor for small vessel disease and later life cognitive impairment. It has an impact on brain structure and function (see H. Suzuki et al., PMID: 29145428). This work, jointly led by DRI Professor Elliott, reports the largest study of genetic risk factors for hypertension to date.
A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target
Srivastava, P.K., van Eyll, J., Godard, P. et al. A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target. Nat Commun 9, 3561 (2018).
Nature Communications
Published 3 September 2018
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This provides a novel bioinformatics framework for generating specific hypotheses for new therapeutics by integrating biological and directly pharmacologically-relevant transcriptomics data. The focus on using pharmacogenomic data related to modulation of GPCRs is intended to better ensure the medicinal chemistry tractability of targets identified. It also allows tool compounds to be identified that might allow early proofs of principle in human experimental medicine. The demonstration of its application in epilepsy- and, indeed, the target identified- well illustrates the potential of the approach to contribute the research in late life neurodegenerative disease.
Molecular Architecture of the Mouse Nervous System
Zeisel A, Hochgerner H, Lönnerberg P, et al. Molecular Architecture of the Mouse Nervous System. Cell. 174(4):999-1014 (2018)
Cell
Published August 2018
Centre Member: Dr Nathan Skene
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This landmark resource paper describes the mapping of cell types and relates these to a hierarchical, data-driven taxonomy. Using single cell transcriptomic methods, it characterises the basis for neuronal cell diversity through differences in cell identity, synaptic connectivity, neurotransmission and membrane conductances.
Architecture of the Mouse Brain Synaptome
Zhu F, Cizeron M, Qiu Z, et al. Architecture of the Mouse Brain Synaptome. Neuron. 99(4):781-799 (2018)
Neuron
Published 2 August 2018
Centre Member: Dr Nathan Skene
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One of the greatest challenges for studies of neurodegenerative disease is to understand how the functional connectional architecture of the brain changes with loss or damage to neurons; expression of disease depends as much on what is preserved and how it works as it does on what is lost. This paper provides the most comprehensive description of the connectional architecture of the mouse brain to date. It provides proofs of concept for developing similar maps with disease models that highlight how the architecture changes. Moreover, it is scalable enough to allow studies with drugs and other interventions. I was delighted that one of our UK DRI scientists, Maksym Kopanitsa, was able to contribute to the work of this exceptional team!
Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.
Savage, J.E., Jansen, P.R., Stringer, S. et al. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence. Nat Genet 50, 912–919 (2018).
Nature Genetics
Published July 2018
Centre Member: Dr Nathan Skene
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This unique genetic association study from new Safra-UK DRI Fellow Skene, identifies the basis of variance in intelligence in genes expressed particularly with stratal medium spiny neutrons and hippocampal pyramidal neurons. Mendelian randomisation suggests protective effects of intelligence for Alzheimer's disease, providing evidence for a causal role for the first time.
Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics
Harris KD, Hochgerner H, Skene NG, et al. Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics. PLoS Biol. 16(6) (2018)
PLoS Biology
Published 18 June 2018
Centre Member: Dr Nathan Skene
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Using novel methods for discrimination of cell-types with single cell transriptomics, this report highlights differences between inhibitory neutrons in the hippocampus, further elucidating the complexity of these inhibitory neutrons.
Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function
Davies, G., Lam, M., Harris, S.E. et al. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Nat Commun 9, 2098 (2018).
Nature Communications
Published 29 May 2018
Centre Member: Prof Paul Elliott
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This landmark study, extending earlier work using distinct mythology, reported by Imperial's Mike Johnson (PMID: 26691832), discovered almost 150 novel genetic loci contributing to the heritability of cognitive functions. Intriguingly, loci implicated in brain structural determination and neurodegeneration were amongst those identified.
A Prospective Metagenomic and Metabolomic Analysis of the Impact of Exercise and/or Whey Protein Supplementation on the Gut Microbiome of Sedentary Adults
Cronin O, Barton W, Skuse P, et al. A Prospective Metagenomic and Metabolomic Analysis of the Impact of Exercise and/or Whey Protein Supplementation on the Gut Microbiome of Sedentary Adults. mSystems. 3(3) (2018)
mSystems
Published 24 April 2018
Centre Member: Prof Elaine Holmes
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A sedentary lifestyle contributes to risks of sporadic onset, late life Alzheimer's disease. The recent FINGER Trial run by Miia Kivipelto, who divides her time between the Karolinska Institute and Imperial, provides direct evidence that a regular programme of exercise as part of a multi domain intervention reduces risks of later cognitive decline (PMID:29055814). This report provides a first prospective analysis of the microbiome with exercise interventions, a key step towards elucidating the potential contribution of the microbiome to slowing cognitive decline with ageing.
Distinguishable brain networks relate disease susceptibility to symptom expression in schizophrenia
Liu Z, Zhang J, Zhang K, et al. 2018, Distinguishable brain networks relate disease susceptibility to symptom expression in schizophrenia, Human Brain Mapping, 39, 3503-3515
Human Brain Mapping
Published 24 April 2018
Centre Member: Prof Paul Matthews
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Using schizophrenia as a model disease, a novel strategy for simultaneous discovery of brain mechanisms contributing to susceptibility and to the variable expression of symptoms of disease was demonstrated.
Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models
Ajami, B., Samusik, N., Wieghofer, P. et al. Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models. Nat Neurosci 21, 541–551 (2018).
Nature Neuroscience
Published 21 April 2018
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This landmark study led by newly recruited UK DRI Fellow Ajami highlighted alpha5 integrin on myeloid cells as a potential target for therapeutic modulation of neuroinflammatory neurodegeneration, but also showed that animal models of Huntington's Disease and Motor Neuron Disease, despite being associated with brain glial activation, were distinguished from experimental allergic encephalitis by a relative lack of trafficking of blood-derived monocytes to the brain.
Genetic Predisposition to High Blood Pressure and Lifestyle Factors: Associations With Midlife Blood Pressure Levels and Cardiovascular Events
Pazoki R, Dehghan A, Evangelou E, et al. Genetic Predisposition to High Blood Pressure and Lifestyle Factors: Associations With Midlife Blood Pressure Levels and Cardiovascular Events. Circulation. 137, 7 :653-661 (2018)
Circulation
Published 13 February 2018
Centre Member: Prof Paul Elliott
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High blood pressure is a known risk factor for dementia. A considerable fraction of the variation in blood pressure is heritable. In this paper, we investigated whether the heritable component of blood pressure could be offset by healthy lifestyle. Our findings support population-wide efforts to lower blood pressure through lifestyle modification which might also contribute to dementia prevention.
Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons
Hervera, A., De Virgiliis, F., Palmisano, I. et al. Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons. Nat Cell Biol 20, 307–319 (2018).
Nature Cell Biology
Published 12 February 2018
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Reactive oxygen species are well-recognised as major factors mediating tissue damage after injury. This report provides new evidence for a previously unrecognised role of ROLS in axonal regeneration through a NOX2-PI3K-pAkt signaling pathway.
Sleep and Sedative States Induced by Targeting the Histamine and Noradrenergic Systems
Yu X, Franks NP, Wisden W. Sleep and Sedative States Induced by Targeting the Histamine and Noradrenergic Systems. Front Neural Circuits. 12:4. (2018)
Frontiers in Neural Circuits
Published 26 January 2018
Centre Members: Prof William Wisden & Prof Nicholas Franks
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This report reviews how different major classes of sedatives- acting as agonists at either the GABA-A or alpha-2 adrenergic receptor- may act through influences on common nodal points of the circuitry promoting wakefulness.
Size-Dependent Axonal Bouton Dynamics following Visual Deprivation In Vivo
Sammons RP, Clopath C, Barnes SJ, Size-dependent axonal bouton dynamics following visual deprivation in vivo, Cell Reports, 22, 576-584 (2018)
Cell Reports
Published 16 January 2018
Centre Member: Dr Samuel Barnes
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Understanding of the rules of normal synaptic plasticity will be needed to understand how this fails in dementias. This report provides important insights into how these mechanisms work at the synaptic level by showing size-dependent (large vs small boutons) plasticity of sensory neutrons in response to sensory deprivation.
Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration
Scott GPT, Zetterberg H, Jolly A, et al. Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration, Brain, 141, 459-471 (2017)
Brain
Published 19 December 2017
Centre Member: Prof Paul Matthews
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This is an important study suggesting the chronic microglial activation associated with later neurodegeneration and cognitive impairment after head injury may be neuroprotection. The UK DRI Professor Matthews and colleagues at Imperial, along with UK DRI Professor Zetterberg from UCL, demonstrated that minocycline, administered to inhibit activation of resident microglia, enhances NfL release, an index of neurodegeneration.
Abnormal brain white matter microstructure is associated with both pre-hypertension and hypertension
Suzuki H, Gao H, Bai W, et al. Abnormal brain white matter microstructure is associated with both pre-hypertension and hypertension. PLoS One. 12,11 (2017)
PLoS One
Published 16 November 2017
Centre Members: Prof Paul Matthews & Prof Paul Elliott
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In the largest brain imaging study of hypertension to date, white matter pathology was identified even with pre-hypertension, emphasising that sustained elevation of blood pressure even to levels previously considered as within a healthy range, can contribute to brain injury and cognitive decline.
Ubiquitin chain conformation regulates recognition and activity of interacting proteins
Ye Y, Blaser G, Horrocks MH, et al. Ubiquitin chain conformation regulates recognition and activity of interacting proteins. Nature. 492(7428):266-70. (2012)
Nature
Published December 2012
Centre Member: Dr Yu Ye
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This fundamentally important report from new UK DRI Fellow Yu shows for the first time that conformational equilibria in ubiquitin chains provide an additional layer of regulation in the ubiquitin system, with distinct conformations observed in differently linked polyubiquitin contributing to determining the specificity of ubiquitin-interacting proteins. This suggests a novel mechanism for "tuning" protein degradation in the cell that could provide a novel mechanism for therapeutic selective enhancement of pathological protein degradation.
Activated microglia do not increase 18 kDa translocator protein (TSPO) expression in the multiple sclerosis brain
11C-BU99008 is a novel positron emission tomography (PET) tracer that enables
selective imaging of astrocyte reactivity in vivo. To explore astrocyte
reactivity associated with Alzheimer's disease, we studied cognitively impaired
(CI) subjects andage-matched healthy controls (HC) with 3T magnetic
resonance imaging (MRI), 18F-florbetaben and 11C-BU99008 PET. Our proof-of-concept study provides direct evidence that
11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life
cognitive impairment and Alzheimer's disease and confirms that increased
astrocyte reactivity is found particularly in cortical regions with high Aβ
load.
Mansur
